OA11012A - 4,10beta-diacetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-9-oxo-19-nor (2r, 3s) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate dihydrate cycloprpaÄgÜtax-ene-13alpha-yl and its preparation process - Google Patents

Abstract

A 4,10 beta -diacetoxy-2 alpha -benzoyloxy-5 beta ,20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa[g]tax-11-ene-13 alpha -yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate, and the preparation thereof by crystallisation from a water-alcohol or water-ketone solution, are disclosed.

Description

011012 1 4,10-DIACETOXY-2a-BENZOYLOXY-5p, 2-EPOXY-1-HYDROXY-9-OXO-19 NOR-C YCLOPROPA [G] TAX-11 -ENE-13a-

YLE, AND PROCESS FOR PREPARING THE SAME

The present invention relates to 4,10-diacetoxy-2a-benzoyl-oxy-5p, 20-epoxy-1-hydroxy-9 (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate. -oxo-19-nor-cyclopropa [g] tax-11-ene-13a-yl, and its preparation.

4,10p-Diacetoxy-2a-benzoyloxy-5p, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate [ g] tax-11-en-13a-yl has remarkable anti-cancer and anti-eukemic properties.

4,10-diacetoxy-2a-benzoyloxy-5p, 20-epoxy-1-hydroxy-9-oxo-19-nor (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate; cyclopropa [g] tax-11-ene-13a-yl is prepared according to the process which is more particularly described in PCT international application WO 94/13654.

It has been found that 4,10-diacetoxy-2a-benzoyloxy-5α, 20-epoxy-1-hydroxy-di (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate 9-oxo-19-nor-cyclopropa [g] tax-11-ene-13a-yl has a stability very much higher than that of the anhydrous product.

According to the invention, 4,10P-diacetoxy-2a-benzoyloxy-5-p-20-epoxy-1-hydroxy-9- (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate -oxo-19-nor-cyclopropa [g] tax-11-ene-13 (x-yl can be obtained by crystallization of (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate 4.10p 2-Diacetoxy-2a-benzoyloxy-5p, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa [g] tax-11-en-13a-yl or by recrystallization of the dihydrate from a water mixture and an aliphatic alcohol containing 1 to 3 carbon atoms, or a mixture of water and a ketone containing 3 to 4 carbon atoms followed by drying 011012 2 under reduced pressure of the isolated product and a possible maintenance in a humidity greater than or equal to 40% or direct drying in an atmosphere with relative humidity greater than or equal to 40%

For carrying out the process according to the invention, it may be particularly advantageous to dissolve (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate of 4,10-diacetoxy-2-en benzoyloxy-5β, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa [g] tax-11-ene-13a-yl or its hydrate in an aliphatic alcohol containing 1 to 3 carbon atoms, or in a ketone containing 3 to 4 carbon atoms, - treat the solution with water, - inoculate the solution with the dihydrate and then treat again with water, - to separate the crystals obtained, then - from the to dry under reduced pressure and then possibly to maintain them in an atmosphere whose relative humidity is greater than or equal to 40%, that is to say, as an example for a relative humidity of 40%, drying under a residual pressure d about 1.33 kPa for a temperature of 25 ° C and a residual pressure of about 3.86 kPa for a temperature of 4 5 ° C. or drying them directly in an atmosphere whose relative humidity is greater than or equal to 40%, that is to say, for example, for a relative humidity of 40%, drying under a residual pressure of about 1.33 kPa for a temperature of 25 ° C and a residual pressure of approximately 3.86 kPa for a temperature of 45 ° C. Generally, 4,10P-diacetoxy-2a-benzoyloxy-5p, 20-epoxy-1-hydroxy-9-oxo-19 (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate -Nor-cyclopropa [g] tax-1-ene-13a-yl or its hydrate is dissolved in an excess of the aliphatic alcohol, preferably ethanol or in an excess of the ketone, preferably acetone. Preferably, the amount of alcohol or ketone is from 4 to 16 parts by volume based on the weight of (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate of 4, 10 diacetoxy-2a-benzoyl-oxy-5β, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa [g] tax-11-ene-13α-ylemis. Generally, the water is added in such a way that the final water / alcohol or water / ketone volume ratio is between 1/3 and 3/1.

4,10p-Diacetoxy-2a-benzoyloxy-5P, 20-epoxy-1-hydroxy-9-oxo-19 (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate -Nor-cyclopropa [g] tax-11-ene-13a-yl which crystallizes is separated, preferably perfiltration or centrifugation. The drying or the optional maintenance in an atmosphere whose relative humidity is greater than or equal to 40% is carried out under reduced pressure, generally between 0.5 and 30 kPa, preferably around 5 kPa at a temperature of between 10 and 70.degree. ° C, preferably close to 40 ° C. The isotherm of water activity of the product has been studied. Thus, 4,10β-diacetoxy-2α-benzoyloxy-5β, 20-epoxy-1-hydroxy-9-oxo-19 (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate -nor-cyclopropa [g] tax-11-ene-13α-yl dihydrate voluntarily dehydrated by thorough drying were maintained in atmospheres of relative humidity (RH) controlled at 25 ° C. Water detectors, determined by ATG, show that the products stabilize at concentrations close to 4% (between 3 and 5%) when the relative humidity is greater than or equal to 40% (theoretical water content of 4.15% for a dihydrate). 011012

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For carrying out the process according to the invention, it is possible to operate directly on the ethanolic solution of (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate of 4.10 g. 2-Diacetoxy-2a-benzoyloxy-5p, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa [g] tax-11-en-13a-yl obtained after deprotection in acidic medium of (2R, 4,10-diacetoxy-2a-benzoyloxy-5p, 20-epoxy-1-hydroxy-4S, 5R) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-oxazolidine-5-carboxylate; 9-oxo-19-nor-cyclopropa [g] tax-1-ene-13a-yl.

The following examples illustrate the present invention. EXAMPLE 1 In a tricolor, 2g of 4,10P-diacetoxy-2a-benzoyloxy-5p, 20-epoxy-1-hydroxy (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate is introduced. 9-oxo-l9-nor-cyclopropane (g) tax-11-ene-13-yl crude and 20 cm 3 of absolute ethanol To the stirred solution at 50 ° C., about 20 cm 3 of water are added over about 45 minutes. then the suspension obtained is cooled to a temperature of 20cC.

After filtration, the product is washed on the filter with 20 ml of absolute ethanol-water (1: 1 by volume), and the product is dried at 40 ° C. under reduced pressure (5.3 kPa). There is obtained 1.64 g of 4,1O-diacetoxy-2a-benzoyloxy-5p-20-epoxy-1-hydroxy-9 (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate. -oxo-19-nor-cyclopropa [g] tax-11-en-13a-yl containing 3.8% by water ATG (theoretical value of the water content of the dihydrate of 4.I5%). The yield obtained is about 80%. The diagram DPRX (x-ray powder diagram) shows that the product thus obtained has the characteristics of the dihydrate.

The X-ray powder diagram is made by means of a P-1700 PIP® apparatus with an anti-cathode cobalt tube (λ = 17889 Å), the scanning being carried out at an initial scan angle of 5 '. 2-9) of a final scan of 40: 2-9 with a step of 0.02 '2-9 at the rate of 1 second in steps and using a desilicon pellet 011012 6 Thermogravimetric analysis (TGA) is carried out by means of Perkin-Elmer TGA 7 * aethermobalance at the initial temperature of 25 ° C. and at a final temperature of 300 ° C. with a temperature gradient of 10 ° C. per minute.

515 g of 4,10-diacetoxy-2a-benzoyloxy-5p (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate are introduced into a nitrogen-purged reactor. epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa [g] tax-11-ene-13a-v lebrut and 4 liters of absolute ethanol. The slurry was heated to 35-40 ° C until dissolution and the reactor was pressurized to 8 kPa. About 8 liters of solvent are distilled at constant volume by continuously feeding the reactor with ethanol (S liters). After delivery of the reactor at atmospheric pressure, the solution is clarified by passing through a filter equipped with a filter cloth of 0.45 μm . After rinsing the filter with 1 liter of absolute ethanol, is added over 1 hour to 40cC on the entire solution about 1.8 liter of water. After priming with 8 g of 4, 10P-diacetoxy-2a-benzoyloxy-5p20-epoxy-1-hydroxy-9-oxo (2R.3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrochloride 19-nor-cyclopropa [g] tax-1-ene-13a-yl. the mixture is cooled to a temperature of 20cC for 15 hours. The suspension is then heated to 40cC and then added in 4 hours 1.66 liter of water. The mixture is cooled to a temperature of 20cC and left stirring for 17 hours. The suspension is filtered on sintered glass and the wrung product is washed with 1.25 liter of an alcohol-water mixture (50-50 by volume). The product is dried in an oven at 35 ° C. under 5.3 kPa for 2 hours in the presence of a water tank then at 35 ° C. under 2. "kPa for 8 hours without reserve of water and again at 35 ° C. under 5.3 kPa for 16 hours in the presence of a reserve of water. 491 g of 4-oxo-diacetoxy-2a-benzoyloxy-5p-20-epoxy-1-hydroxy-9-oxo (2R, 3S) -5-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate are thus obtained. 19-nor-cyclopropa (g) tax-1-en-13a-yl containing 4.0% water (KariFischer) .The DPRX diagram (X-ray powder diagram) shows that the product thus obtained is in the form of a dihydrate (theoretical value of the water content of 4,10-diacetoxy-2a-benzoyloxy (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate; 5β, 20-epoxy-1-hydroxy-9-oxo-9-nor-cyclohexyl [g] tax-11-ene-13-yl of 4.15%).

The X-ray powder diagram is made under the conditions described in Example 1. EXAMPLE 3

3 g of (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate of 4,10P-diacetoxy-2a-benzoyloxy-5β, 20-έροχγ- 1-hydroxy-9-oxo-19-nor-cyclopropane [g] tax-11-ene-13a-yl crude and 10 cm3 of acetone. To the resulting solution which is stirred at a temperature of 20 ° C, 20 cm3 of water are added over about 35 minutes. The resulting suspension is stirred for about 15 minutes. After filtration, the product is washed twice on the filter with 20 cm3 of an acetone-water mixture (1-1 by volume), and the product is dried at 40 ° C. under reduced pressure (5.3 kPa). There is thus obtained 1.28 g of 4.10β-diae-2α-benzoyloxy-5p, 20-epoxy-1-hydroxy-9 (2R.3 S) -3-tert-butoxycarbonylamino-2-hydroxyl-3-phenylpropionate dihydrate. -oxo-19-nor-cyclopropyl [g] tax-1-ene-13-yl. The yield obtained is about 75%. The diagram DPRX (X-ray powder diagram) shows that the product thus obtained has the characteristics of the dihydrate. The X-ray powder diagram is made under the conditions described in Example 1. EXAMPLE -i

In a nitrogen-purged reactor, 120 g of (4-oxo-4-methoxyphenyl) -4-phenyloxazolidine-5-carboxy late-4-oxo-diacetoxy (120 g) are introduced. 2H-benzoyloxy-5p-20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropanol-1-en-1-en-yl and 1.08 liters of ethyl acetate The suspension is stirred at a temperature in the region of 20 ° C., then a solution of 3.25 cm 3 of 36% hydrochloric acid in 17.6 cm 3 of water is introduced, After standing for 3 hours 50 8 0110 12 minutes, a solution of 3 is charged into the reactor. 5 g of sodium hydrogencarbonate in 350 cm3 of water and stirred for 15 minutes After decantation and drawing off of the aqueous phase, the mixture is washed twice with 350 cm 3 of water, and the organic phase is concentrated under reduced pressure. at about 25 ° C. to a residual volume of 350 cm 3, then 350 cm 3 of absolute ethanol are introduced, the distillation under reduced pressure is resumed at about 30 ° C. until exhausted. ethyl acetate by feeding with 1.5 liters of absolute ethanol. The solution is heated to 40 ° C. and 470 cm3 of water are then added over 15 minutes. The solution is inoculated with a suspension of 1 g of 4,10-diacetoxy-2a-benzoyloxy-5p (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate, 20-epoxy. -1-hydroxy-9-oxo-19-nor-cyclopropa [g] tax-11-en-13a-yl in a mixture of 40 cm3 of water and 40 cm3 of absolute ethanol. After standing for 15 hours at approximately 40 ° C., 4 l0 cm3 of water are added over 4-5 hours and then the suspension is cooled to 20 ° C. After filtering and washing the product on a filter, the product is dried for 15 hours under reduced pressure (2.7 kPa) at 25 ° C. and then for 24 hours at 35 ° C. 102 g of (2R, 3S) dihydrate are thus obtained. 4α-Diacetoxy-2α-benzoyloxy-5α-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa [g] tetra-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate en-13a-yl, containing 4.3% water (Karl Fischer), with a yield of about 93%. The diagram DPRX (X-ray powder diagram) shows that the product thus obtained has the characteristics of the dihydrate.

The X-ray powder diagram is made under the conditions described in Example 1.

Claims (6)

1 - 4,10P-Diacetoxy-2a-benzoyloxy-5P, 20-epoxy-1-hydroxy-9-oxo-19 (2R.3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate -Nor-cyclopropa [g] tax-11-ene-13a-yl. 2 - Process for the preparation of 4,10-diacetoxy-2a-benzoyl-oxy-5p, 20-epoxy-1-hydroxy-di (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate 9-oxo-19-nor-cyclopropane [g] tax-11-en-13a-y characterized in that (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate is crystallized from of 4,10-diacetoxy-2a-benzoyloxy-5p, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa [g] tax-11-en-13a-yl or its hydrate in a mixture of water and an aliphatic alcohol containing 1 to 3 carbon atoms or in a mixture of water and a ketone containing 3 to 4 carbon atoms, which is dried under reduced pressure and maintained optionally in relative humidity conditions greater than or equal to 40%. or that the product is dried directly under relative humidity conditions greater than or equal to 40%. 3 - Process according to claim 2 characterized in that the final volume ratio water / alcohol and water / ketone is between 3/1 to 1 3. 4 - Process according to one of claims 2 or 3 characterized in that the alcohol is ethanol and the ketone is acetone. 5 - Process according to claim 2 characterized in that the drying or the eventual maintenance under a relative humidity greater than or equal to 40 'o is carried out at a temperature of 40 ° C under a pressure close to 5 kPa and the productis stabilized in these conditions between 3 and 5% water. 6 - Process according to claim 2 characterized in that one operates directly from the ethanolic solution of (2R.3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate 4.10p-diacétoxy-2a- ΙΟ 011012 Benzoyl-oxy-5P, 20-epoxy-1-hydroxy-9-oxo-19-nor-cyclopropa [g] tax-11-en-13a-y obtained by acidic deprotection of the ester (2R, 4S 4,10β-Diacetoxy-2α-benzoyl-oxy-5β, 20-epoxy-1-hydroxy-5α, 5R) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyloxazolidine-5-carboxylate; 9-oxo-19-nor-cyclopropa [g] tax-11-en-13a-yl.